Epidermal Growth Factor Receptor (EGFR) is overexpressed in a variety of solid human tumors including non-small-cell-lung-carcinoma, breast cancer, glioblastoma, head and neck squamous cell carcinoma, colorectal cancer, adenocarcinoma, ovary cancer, bladder cancer and prostate cancer (Hynes et al., 2009). The American Cancer Society's annual estimate of new cancer cases and deaths projects 1,437,180 new cancer cases in the United States in 2008 and 565,650 cancer deaths. The cause of most cancer deaths is metastasis of the cancer into internal organs, which is virtually impossible to treat by conventional methods. A significant fraction of all cancer related deaths are associated with overexpression of EGFR. Thus EGFR is one of the most important candidates for targeted cancer therapy.
The two most advanced EGFR-targeted therapies are small membrane permeable EGFR kinase inhibitors and anti-EGFR antibodies, which prevent receptor activation and/or lead to receptor down-regulation. These agents induce temporary or partial remission and convey some survival benefits, but do not actually cure patients. This is most likely because EGFR is not essential for the survival of the targeted cancer cells.
PolyIC, a synthetic polyinosinic-polycytidylic acid double-stranded RNA, is a known cytotoxic agent. Intratumoral or peritumoral administration of non-targeted PolyIC has been demonstrated to be effective in anti-tumor immunotherapy (Fujimura et al., 2006). Such treatment is limited to localized tumors only as has been shown by attempts to systemic application of non-targeted PolyIC to treat cancer. The survival benefit was minimal while pronounced systemic toxicity was observed (Butowski et al., 2009; Salazar et al., 1996). The weak effect was most likely caused by the failure to introduce a sufficient dose of PolyIC into the tumor cells. Most of the non-targeted PolyIC probably scattered through normal tissues entering into non-cancer cells and inducing toxic reactions.
Recently we developed a strategy that utilizes the high level of expression of EGFR, rather than its activity per se, as the Achilles' heel of the tumor. This was achieved by utilizing an EGFR homing chemical vector loaded with PolyIC (Shir et al., 2006; WO 04/045491). The intratumoral application of PolyIC/Melittin-Polyethyleneimine-Polyethyleneglycol-EGF (PolyIC/MPPE) to EGFR overexpressing glioblastoma (˜1×106 receptors/cell) grown intracranially and to EGFR overexpressing breast and epidermoid carcinomas grown as xenografts in nude mice, led to complete elimination of these localized tumors, curing the mice. Furthermore, tumors comprising a 1:1 mixture of cells overexpressing wild type EGFR and cells harboring the mutant EGFRvIII, which does not internalize the vector, were also completely eradicated. This “bystander effect” was due to the antiproliferative cytokines such as interferon-α, generated at the tumor site by the PolyIC/MPPE affected tumor cells.